Chemotherapy with drugs conjugated to monoclonal antibodies appears promising because specific antibodies can be produced against well characterized and isolated, tumor-associated antigens. Because of the specificity of antibodies, this type of therapy is expected to reduce or eliminate the toxicity of currently used chemotherapeutic drugs. Following Kohler and Milstein's work with hybridomas that produce monoclonal antibodies (Kohler, G., and Milstein, C., "Continuous cultures of fused cells secreting antibody of predefined specificity," Nature 256, 495-497 (1975)) several monoclonal antibody-drug conjugates have been synthesized for treating a variety of murine and human tumors in vitro and in vivo.
Doxorubicin is active against ovarian cancer and its molecular structure has been well established. In 1975, Hurwitz, et al. first chemically modified the amino sugar ring of doxorubicin in attempts to link the drug to an antibody. Hurwitz, E., et al., "The covalent binding of daunomycin and Adriamycin to antibodies with retention of both drug and antibody activities," Cancer Res. 35, 1175-1181 (1975). Unfortunately, their use of sodium periodate which ruptures the sugar ring also causes other structural changes with concommitant loss of cytotoxic activity. Since these early efforts, the chemistry of linker technology has focused on utilizing the intact sugar group or the side chain at the C-9 position. Yang, H. M., and Reisfeld, R. A., "Doxorubicin conjugated with monoclonal antibody directed to a human melanoma-associated proteoglycan suppresses the growth of established tumor xenografts in nude mice," Proc. Natl. Acad. Sci. 85, 1189-1193 (1988). Pietersz, C. A., Smyth, M. J., and McKenzie, I.F.C., "Immunochemotherapy of a murine thyoma with the use of idarubicin monoclonal antibody conjugates," Cancer Res. 48, 926-9311 (1988).
The ideal drug-antibody conjugate will specifically transport the drug to the cancer cells and the targeted drug will exhibit its usual toxicity. Such an ideal set of conditions will increase the therapeutic index of the drug. The anthracycline antibiotics have the widest spectrum of antitumor activity of all present chemotherapeutic agents. Daunorubicin and doxorubicin show efficacy towards leukemias and solid tumors respectively. An accepted mechanism by which daunorubicin inhibits cell growth is associated with the intercalation of the drug in DNA which interferes with mitosis. A second mechanism of inhibition of cell growth is associated with the tendency of anthracyline antibiotics to generate free radicals that are capable of disrupting cell membranes and electron transport. Doxorubicin is employed in the most widely accepted chemotherapeutic regimen for treating ovarian carcinoma, namely, cisplatin-doxorubicincyclophosphamide.
U.S. Pat. No. 4,093,607 to Sela et al. (1978), relates generally to antitumor drug-antibody conjugates and more particularly to conjugates to anticancer antibiotics such as daunomycin and doxorubicin and antigen binding dimers derived by proteolytic digestion of an immumoglobulin containing an antibody specific to a tumor antigen.